Field of the Invention
The present invention relates to compounds, compositions, and methods of use for the inhibition of checkpoint gene expression or for diagnosing, treating and/or preventing diseases and/or conditions that respond to the inhibition of checkpoint gene expression.
Summary of the Related Art
The immune system is a hosts defense against foreign antigens; however, in order to function properly a variety of checks and balances are required to protect against self-antigens (i.e., autoimmunity) and, at the same time, provide an appropriate response against foreign. Immune-activating and immune-suppressive receptors and ligands provide these regulatory checks and balances (see Pardoll et al., The blockade of immune checkpoints in cancer immunotherapy, Nat. Rev. Canc. 12, 252 (2012)).
Immune checkpoints refer to a group of endogenous immune-suppressive ligands and receptors that are crucial for the maintenance of self-tolerance and the protection of tissues from damage when the immune system is responding to an infection. (see Y. L. Wu, et al., Immunotherapies: The Blockade of Inhibitory Signals, Int. J. Biol. Sci. 8, 1420 (2012)) In response to the induction of an immune response expression of checkpoints increases. These checkpoints act as regulatory feedback to maintain immune homeostasis.
In patients with cancer, tumor mutations give rise to tumor-specific antigens that can be recognized by the immune system, particularly T-cells, leading to elimination of cancer cells. However, to defend themselves, tumor cells can co-opt immune checkpoint pathways to suppress the immune response in the tumor microenvironment and evade the host immune system by inhibiting T cells that might otherwise attack the tumor cells. (see J. F. Grosso & M. N. Jure-Kunkel; CTLA-4 blockade in tumor models: an overview of preclinical and translational research, Cancer Immun. 13, 5 (2013); M. E. Turnis, et al.; Combinatorial immunotherapy: PD-1 may not be LAG-ing behind any more, OncoImmunology 1, 1172 (2012)).
Many previous cancer immunotherapies have likely been limited by these suppressive mechanisms. Thus there is a need to over these immunosuppressive mechanisms in order to enhance antitumor immunotherapy applications.